Pharmaceutical composition essentially containing and method of treatment with,3 beta-acetoxy 11-oxo noroleanene-(12) 20 beta-carboxylic acid n-methyl piperidol-(4) ester

ABSTRACT

3-B-Acetoxy 11-oxo noroleanene-(12) 20B-carboxylic acid N-methyl piperidol-(4) ester and physiologically tolerable acid addition salts thereof that are orally administerable and have superior inflammation inhibiting and ulcer inhibiting properties.

United States Patent [19 Kraft et al.

[111 3,812,258 1451 May 21,1974

[ PHARMACEUTICAL COMPOSITION ESSENTIALLY CONTAINING AND METHOD OF TREATMENT WITH, 3 BETA-ACETOXY ll-OXO NOROLEANENE-( 12) 20 BETA-CARBOXYLIC ACID N-METHYL PIPERIDOL-(4) ESTER [75] Inventors: Helmut Kraft, Neckarhausen; Frank Zimmermann, Mannheim; Hans-Peter Hotmann, Ludwigshafen, all of Germany [73] Assignee: Knoll AG, Chemische Fabriken,

Ludwigshafen/Rhein, Germany 221 Filed: Nov. 27, 1972 21 Appl. Non 309,750

Related US. Application Data [62] Division of Ser. No. 174,924,Ai1g. 25, 1971, Pat. No.

[30] Foreign Application Priority Data Sept. 2, 1970 Germany 2043479 [52] US. Cl. 424/267 Primary Examiner-Albert T. Meyers Assistant Examiner-Frederick E. Waddell Attorney, Agent, or FirmCurtis, Morris & Safford [5 7] ABSTRACT 3-B-Acetoxy ll-oxo noroleanene-( l2) 2OB-carboxylic acid N-methyl piperidol-(4) ester and physiologically tolerable acid addition salts thereof that are orally administerable and have superior inflammation inhibiting and ulcer inhibiting properties..

3 Claims, No Drawings PHARMACEUTICAL COMPOSITION ESSENTIALLY CONTAINING AND METHOD OF TREATMENT WITH, 3 BETA-ACETOXY l1-0X0 NOROLEANENE-(IZ) ZUBETA-CARBOXYLIC ACID N-METHYL PIPERIDOL-(4) ESTER This is a division of application Ser. No. 174,924 filed Aug. 25, 1971 now US. Pat. No. 3,758,484.

The present invention relates to a derivative of glycyrrhetinic acid, a process for the preparation thereof and a pharmaceutical composition containing such a derivative.

It is known from the work of R. S. H. Finney and G. F. Somcrs [.l. Pharm. Pharmacol. 10, 613 (195 8)] that glycyrahetinic acid [3B-hydroxy ll-oxo noroleanene- (12) 20Bcarboxylic acid] has inflammation inhibiting properties. The introduction of an acetyl group into the 3-position of glycyrrhetinic acid does not change the strength of the inflammation inhibiting effect.

It has now been discovered that a certain ester of 3,8- acetoxy glycyrrhetinic acid has very good inflammation-inhibiting properties. i

The present invention therefore is concerned with 3,8-acetoxy 1 l-oxo noroleanene-( l2) ZOB-carboxylic acid N-methyl-piperidol-(4)-ester of the formula CH: CH3

CH3 onto O O CH:

H; C CH:

and the salts thereof formed with patible acids.

The present invention is also concerned with a method for the preparation of the above compound and its salts wherein 3l3-acetoxy ll'oxo noroleanene- (12) 20B-carboxylic acid (or a functional derivative thereof) is reacted withN-methyl pipenidol-(4). If dephysiologically (comsired, the resultant ester may then be converted into the salt of a physiologically compatible acid. The esterification can be performed according to methods known per se. Esterification occurs in high yields if the acid is converted into its chloride and then reacted with N- methyl-piperidol-(4).

The following are among acids considered to be neimittelforschung 4, 341 (1954) and of the acid se' cretion in rats whose Pylorus was ligated. [l-l. Shay, S. A. Komaroy, S. S. Fels, D. Meranze, M. Gruenstein and H. Siplet, Gastroenterology 5, 43 1945)]. With regard to the ulcer protective effect, the new compound and its salts are approximately ten times stronger than Carbenoxolon (sodium salt). In the LungOedema test [according to D. Henschler, W. Ross, Naunyn. Schmiedebergs Arch. exp. Path. Pharmakoll. 241, 159 (1961)] the new substances show themselves to beapproximately twice as strong as the Carbenoxolon (sodium salt).

Furthermore, the new substances are eight to times more compatible than the sodium salt of Carbenoxolon, as shown by the determination of the acute toxicity in the Albino mouse (NMRl) after a single era] does according to D. J. Finney (Probit Analysis 1962).

when taken orally in doses of approximately 1 10 mg/kg per day.

EXAMPLE 1 A mixture of 3B-acetoxy-ll-oxo-noroleanene-(IZ) 20B-carboxylic acid chloride (8g, 0.015 mol), N- methyl-piperidol-(4) (3.62g, 0.032 mol) and toluene (180 ml) is boiled under reflux for 12 hours. After cooling, N-methyl-piperidol-(4)-hydrochloride which has separated out, is filtered off and diethyl ether (180ml) is added to the filtrate. By passing HCl gas therethrough, the hydrochloride of 3Bacetoxy-1 l-oxonoroleanene-( l2)-20B-carboxylic-acid-N-methyl piperidol-(4)-ester is precipitated. A yield of 9. lg, representing 94 percent'of the theoretical yield is obtained. The compound has an empirical formula of C H NO HCl and a molecular weight of 646.33.

The product is recrystallized from isopropanol and yields colorless crystals having a melting point of 298300 C, and an [a] D of 118.1 (Dimethylformamide, C 0.5).

EXAMPLE 2 A mixture of 3B-acetoxy ll-oxo noroleanene-( l2) ZOB-carboxylic acid chloride (8g, 0.015 mol), N- methyl piperidol-(4) (3.62g, 0.032 mol) and toluene (180 ml) is boiled under reflux r0 12 hours. After cooling, N-methyl. piperidal-(4) hydrochloride, which has separated out, is filtered off and. the filtrate is evaporated to dryness. The residue is recrystallized twice from a mixture of cyclohexane and n-hexane in a ratio of 1:5. 3B-acetoxy ll-oxo noroleanene-(lZ) 200- carboxylic acid N-methyl piperidol (4) ester is ob tained in a yield representing percent of the theoret ical yield. The compound has an empirical formula of C ,,H NO a molecular weight of 609.9, a melting point of 22022l C and an [a] D of l27.l (Dimethylformamide, C 0.5

By reacting with the corresponding free acids, the following salts may be'obtained:

Sulfate C H NO H SO molecular weight 707.94, having a melting point of 268 to 269 C when recrystallized from isopropanol [a] D +107.6 (Dimethylformamide, c 0.5)

from isopropanol [a] D +96.4 (Dimethylformamide c 0.5)

EXAMPLE 3 Tablets of the following composition are formed by pressing on a tablet press:

50.00 mg 3 -Acetoxy l loxo norolcanene-( l2) ZOB-carboxylic acid N-methyl piperidol-(4) estcr hydrochloride Maize starch 4.50 mg Gelatine 15.00 mg Lactose 7.50 mg Talc 0.75 mg Aerosil (Registered Trade Mark) (chemically pure silicic acid in submicroscopically fine particles) Potato starch (as a 6% paste) EXAMPLE 4 Sugar coated pills of the following compositions are prepared in the usual manner:

35.00 mg Sfi-Acetoxy l l-oxo noruleanenc-( l2) 20fl-carboxylic 85.00 mg 80.00 mg The core material consists of nine parts maize starch,

three parts lactose and one part Luviscol VA 64 (Registered Trade Mark) (vinylpyrrolidone-vinyl acetate mixed polymerisate in a 60 40 ratio, Pharm. Ind. 1962 586). The sweetening consists of five parts cane sugar, two parts maize starch, two parts calcium carbonate and one part tale. The resultant sugar coated pills are then provided with a gastric juice-resistant coating.

We claim:

1. An inflammatoryand ulcer-inhibiting pharmaceutical composition comprising, as the active compound, an effective inflammatory-and ulcer-inhibiting amount of 3Bacetoxy-l l-oxo noroleanene-( l2)-20B-carboxylic acid N-methyl piperidol-(4) ester or a salt thereof with a physiologically compatible acid and a therapeutically acceptable carrier.

2. A method of treating gastric or duodenal ulcers in a sufferer thereof which comprises the oral administration to said sufferer of an effective amount of the active compound identified in claim 1.

3. The method of claim 2 in which the effective amount is a dosage unit of about 1 to 10 mg/kg/day.

* =l l =l =l 

2. A method of treating gastric or duodenal ulcers in a sufferer thereof which comprises the oral administration to said sufferer of an effective amount of the active compound identified in claim
 3. The method of claim 2 in which the effective amount is a dosage unit of about 1 to 10 mg/kg/day. 